Interleukin-13 (IL-13) is a cytokine expressed in inflammatory immune responses that are controlled by Th2-type T lymphocytes (Minty et al. (1993) Nature 362, 248-250; McKenzie et al. (1993) Proc. Natl. Acad. Sci. USA 90, 3735-3739). Recently it has been suggested that IL-13 plays a central role in the pathogenesis of asthma (Wills-Karp et al. (1998) Science 282, 2258-2261; Grunig et al. (1998) Science 282, 2261-2263) and transgenic expression of IL-13 in the lung produced an asthmatic like response (Zhu et al. (1999) J. Clin. Invest. 103, 779-788). IL-13 expression is also found to be elevated in asthma patients (Walker et al. (1992) Am. Rev. Respir. Dis. 146, 109-115; Humbert et al. (1997) J. Allergy Clin. Immunol. 99, 657-665; Huang (1995) J. Immunol. 155, 2688-2694) and asthma has been genetically linked to chromosome 5q, a region that contains both the IL-13 and the IL-9 genes (Marsh et al. (1996) Science 264, 1152-1156).
Based on the data presented in the patent applications listed above, there is substantial support for the role of the cytoline IL-9 in the pathogenesis of asthma. First, applicants demonstrate linkage homology between humans and mice, suggesting the same gene is responsible for producing biologic variability in response to antigen in both species. Second, differences in expression of the murine IL-9 candidate gene are associated with biologic variability in bronchial responsiveness. In particular, reduced expression of IL-9 is associated with a lower baseline bronchial response in B6 mice. Third, recent evidence for linkage disequilibrium in data from humans suggests IL-9 may be associated with atopy and bronchial hyperresponsiveness consistent with a role for this gene in both species (Doull et al. (1996) Am. J. Respir. Crit. Care Med. 153, 1280-1284). Moreover, applicants have demonstrated that a genetic alteration in the human gene appears to be associated with loss of cytokine function and lower IgE levels. Fourth, the pleiotropic functions of this cytokine and its receptor in the allergic immune response strongly support a role for the IL-9 pathway in the complex pathogenesis of asthma. Fifth, in humans, biologic variability in the IL-9 receptor also appears to be associated with atopic allergy and asthma. Finally, despite the inherited loss of IL-9 receptor function, these individuals appear to be otherwise healthy. Thus, nature has demonstrated in atopic individuals that the therapeutic down-regulation of IL-9 and IL-9 receptor genes or genes activated by IL-9 and its receptor is likely to be safe and useful for the treatment of asthma.
In some infectious diseases it has recently been suggested that elevated levels of IL-13 may contribute to the pathogenesis of the disease. For example, in patients with tuberculosis it has been demonstrated that there is a very large relative increase in IL-4 and IL-13 expression, that correlates with lung damage and indicates that a T helper-2 (Th2) component in the response to M. tuberculosis may undermine the efficacy of immunity and contribute to immunopathology (Rook et al. (2001) Curr. Opin. Pulm. Med. 7, 116-123). In addition, in patients with dengue hemorrhagic fever it has been suggested that high levels of IL-13 may contribute to the shift from a Th1 to Th2 type response and thus to the pathogenesis of the disease (Mustafa et al. (2001) FEMS Immunol. Med. Microbiol. 30, 229-233).
High levels of IL-13 have also associated with diseases that are characterized by fibrosis (Oriente et al. (2000) J. Pharmacol. Exp. Ther. 292, 988-994), for example Hodgkin's disease (Ohshima et al. (2001) Histopathology 38, 368-375).
IL-13 has also been shown to be capable of up-regulating the enzyme 15-lipoxygnase and the down-regulation of its isozyme 5-lipoxygenase (Nassar et al. (1994) J. Biol. Chem. 269, 27631-27634; Spanbroek et al. (2001) Proc. Natl. Acad. Sci. USA 98, 5152-5157). The net effect appears to be the down-regulation of a Th1 mediated inflammatory response.
It has previously been shown that IL-9 is important in asthma and other inflammatory diseases. The present invention is based, in part, upon the discovery described herein that control IL-9 levels can be utilized to control IL-13 levels in inflammatory diseases such as asthma.